Regulation of Human Innate Lymphoid Cells in the Context of Mucosal Inflammation

Abstract

Since their identification as a unique cell population, innate lymphoid cells (ILCs) have revolutionized our understanding of immune responses, leaving their impact on multiple inflammatory and fibrotic pathologies without doubt. Thus, a tightly controlled regulation of local ILC numbers and their activity is of crucial importance. Even though this has been extensively studied in murine ILCs in the last few years, our knowledge of human ILCs is still lagging behind. Our review article will therefore summarize recent insights into the function of human ILCs and will particularly focus on their regulation under inflammatory conditions. The quality and intensity of ILC involvement into local immune responses at mucosal sites of the human body can potentially be modulated via three different axes: (1) activation of tissue-resident mature ILCs, (2) plasticity and local transdifferentiation of specific ILC subsets, and (3) tissue migration and accumulation of peripheral ILCs. Despite a still ongoing scientific effort in this field, already existing data on the fate of human ILCs under different pathologic conditions clearly indicate that all three of these mechanisms are of relevance for the clinical course of chronic inflammatory and autoimmune diseases and might likewise provide new target structures for future therapeutic strategies.

Elevated ILC3s-related Inflammatory Factors may Promote Tendinopathy

“…ILC is de ned by characteristic antigens expressed on its surface, characteristic cytokines secreted by it, and speci c transcription factors. For example, human ILC1s express CD56 to secrete IFN-γ, and their transcription factor is T-beta [20]; ILC2s express CRTH2 to secrete IL-13, and their transcription factor is RORA [21]; and ILC3s express IL-23R, secrete IL-17A, and their transcription factor is RORC [22]. As shown in Fig.…”

Elevated ILC3s-related Inflammatory Factors May Promote Tendinopathy

“…ILC is de ned by characteristic antigens expressed on its surface, characteristic cytokines secreted by it, and speci c transcription factors. For example, human ILC1s express CD56 to secrete IFN-γ, and their transcription factor is T-beta [20]; ILC2s express CRTH2 to secrete IL-13, and their transcription factor is RORA [21]; and ILC3s express IL-23R, secrete IL-17A, and their transcription factor is RORC [22]. As shown in Figure 3A and B, the expression of CD45, a common leukocyte differentiation marker, was upregulated; additionally, the expression of IL-23R, a surface marker of ILC3s, was also upregulated relative to tendon tissues from control patients.…”

“…The ow staining protocol for ILC3s consists of a variety of protocols. In this study, our staining protocol de nes ILC3s as Lin − IL-2R + IL-23R + , which is commonly used in the ow cytometry detection of ILC3s [22].…”

Innate Lymphoid Cells as Regulators of Epithelial Integrity: Therapeutic Implications for Inflammatory Bowel Diseases

“…Especially in CD patients an enhanced percentage of intestinal ILC1s has been described in multiple studies ( 17 , 34 , 44 ) and was obviously associated with an advanced disease severity ( 34 ). Regarding the underlying mechanism for the accumulation of ILC1s in the inflamed intestine of CD patients, transdifferentiation of other ILC subtypes into ILC1s was suggested to take place in the IL-12-enriched microenvironment of the inflamed gut of CD patients ( 25 ). In in vitro experiments, ILC2s, ILC3s as well as c-Kit + NKp44 − immature ILCs were described to transdifferentiate into IFN-γ-secreting ILC1-like cells in the presence of IL-12 ( 17 , 36 , 47 – 50 ).…”

“…Finally, ILC3s depend on the transcription factor RORγt and can be subdivided into lymphoid tissue inducer (LTi) cells, which play a significant role during lymphoid organogenesis, as well as NCR + and NCR − ILC3s as relevant producers of IL-17A, IL-22, and GM-CSF at mucosal sites, appearing accordingly in many functional aspects like innate counterparts of Th17 cells ( 22 , 23 ). An important functional attribute, which is common to all local helper ILC pools in mucosal organs, is their early activation in response to pathological tissue damage and their subsequent capacity to support, amplify, and modulate local adaptive immune responses ( 24 , 25 ). While this sequential cascade of primary or externally triggered epithelial damage, subsequent ILC activation via epithelial cell-released factors and, finally, the ILC-mediated modulation of adaptive immune responses has drawn a lot of scientific attention during the last decade ( 15 , 24 , 26 , 27 ), the opposite direction, meaning the ILC-to-epithelium communication, often seemed to fade a bit into the background.…”